Structure-based drug discovery of carbonic anhydrase inhibitors

Supuran, Claudiu T.

doi:10.3109/14756366.2012.672983

Cited by 565 publications

(462 citation statements)

References 86 publications

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“…These inhibitor discovery processes are complemented by more precise methods in small-molecule inhibitor design. Structure-based methods rely on the use of x-ray crystallographic or NMRbased structures of a protein of interest to design small molecules likely to bind and inhibit protein function [9,10]. Computer-aided inhibitor design uses computational methods to optimize potential inhibitors identified by screening or structure-based methods, to virtually screen for new inhibitors from large libraries and to design potential inhibitors from databases of known protein-ligand interactions [11,12].…”

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confidence: 99%

Small-Molecule Inhibitors of Myosin Proteins

et al. 2012

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Advances in screening and computational methods have enhanced recent efforts to discover/ design small-molecule protein inhibitors. One attractive target for inhibition is the myosin family of motor proteins. Myosins function in a wide variety of cellular processes, from intracellular trafficking to cell motility, and are implicated in several human diseases (e.g., cancer, hypertrophic cardiomyopathy, deafness and many neurological disorders). Potent and selective myosin inhibitors are, therefore, not only a tool for understanding myosin function, but are also a resource for developing treatments for diseases involving myosin dysfunction or overactivity. This review will provide a brief overview of the characteristics and scientific/therapeutic applications of the presently identified small-molecule myosin inhibitors before discussing the future of myosin inhibitor and activator design.The identification and characterization of pharmacological compounds that inhibit the functional activity of one or more specific proteins or processes has been the subject of much scientific investigation. On a basic science level, these membrane-permeable compounds provide the scientific community with a tool for the targeted and functional inhibition of a given protein in the cell; a potent means of evaluating the intracellular functions of that protein [1,2]. From a biomedical standpoint, the characterization of these small-molecule inhibitors affords an opportunity for the development of novel disease treatments centering on the repression of an offensive molecule or the reversal of its downstream effects [3][4][5].At present, several complementary methods for obtaining suitable small-molecule inhibitors of specific proteins exist. Traditional methods in inhibitor discovery involve the systematic testing of a series of chemically synthesized or naturally occurring compounds. Advances in robotics and data processing have made it possible to use high-throughput screens to test libraries of thousands or even millions of potential drugs for their ability to inhibit the function of a specific protein in a targeted biochemical or cellular assay [6][7][8]. These inhibitor discovery processes are complemented by more precise methods in small-molecule inhibitor design. Structure-based methods rely on the use of x-ray crystallographic or NMRbased structures of a protein of interest to design small molecules likely to bind and inhibit protein function [9,10]. Computer-aided inhibitor design uses computational methods to optimize potential inhibitors identified by screening or structure-based methods, to virtually © 2013 Folma Buss * Author for correspondence: Tel.: +44 1223 763348, Fax: +44 1223 762640, fb207@cam.ac.uk. Financial & competing interests disclosureThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance w...

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confidence: 99%

Small-Molecule Inhibitors of Myosin Proteins

et al. 2012

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“…The crystal structure was determined at pH 8.0, when a bicarbonate ion bound in a non-catalytic binding pocket close to the zinc ion was also observed [48]. At pH 8.3, the enzyme showed a significant catalytic activity for the physiological reaction of CO 2 [63].This is in fact the situation for all type II β-CAs, which at pH values > 8 become of type I, with the asp residue being involved in a salt bridge with a neighboring conserved Arg, and an incoming water molecule/hydroxide ion replacing the Asp residue [49][50][51][52][53][54]. Recently it was reported that sodium bicarbonate induces cholera toxin (CT) expression [64,65].…”

Section: Vibrio Choleraementioning

confidence: 85%

“…These compounds were also investigated for the inhibition of some pathogenic CAs such as those of Mycobacterium tuberculosis, Porphyromonas gingivalis, etc. [1,47,52,53]. The DTCs showed effective CA inhibitory activity against many bacterial enzymes (Fig.…”

Section: Dithiocarbamatesmentioning

confidence: 99%

Inhibition of Bacterial Carbonic Anhydrases as a Novel Approach to Escape Drug Resistance

Capasso

Supuran

2017

CTMC

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Background: Clinically used antibiotics act through one of these four mechanisms: cell wall biosynthesis inhibition, inhibition of protein biosynthesis, interference with DNA and RNA synthesis and the folate pathway. Objective:The metalloenzymes carbonic anhydrases (CAs, EC 4.2.1.1) widespread in microorganisms and present as three genetically distinct families may be considered for the design of antiinfective agents with a different mechanism of action compared to the clinically used antibiotics. CAs are crucial for the life cycle of the pathogen, interfering with pH regulation and biosynthetic processes in which CO 2 or bicarbonate are substrates. CA inhibition was shown to lead to debilitation or growth defects of several pathogenic bacteria. Method:CAs catalyzes the interconversion between carbon dioxide to bicarbonate, leading to the formation of protons, and thus affecting pH homeostasis. Several classes of CA inhibitors (CAIs) are known to date, among which the metal complexing anions, the unsubstituted sulfonamides, the dithiocarbamates, etc., which bind to the Zn(II) ion of the enzyme either by substituting the non-protein zinc ligand or add to the metal coordination sphere.Results: Effective inhibitors for many bacterial CAs belonging to the α-, β-, and γ-CA classes were detected, some of which inhibited bacterial growth in vivo. Few of the inhibitors investigated so far were also selective for the bacterial over the human CA isoforms, which may pose problems for their wide clinical applications. Conclusion:Structure-based drug design campaigns might lead to the achievement of the desired selectivity/potency for preferentially inhibiting bacterial but not the host CAs.

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“…Carbonic anhydrases (CA) are ubiquitous metalloenzymes that involved in various physiological and pathological processes, serving as an important target for designing drugs useful in diseases like epilepsy and cancer [111][112][113][114][115]. Recent research has shown that several CA isozymes are drug targets for cancer and infective diseases.…”

Section: 3 5-triazine Derivatives Targeting Hca IX and Hca Xiimentioning

confidence: 99%

A Systematic Review on Antitumor Agents with 1, 3, 5-triazines

Liu¹

2015

Med chem

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Structure-based drug discovery of carbonic anhydrase inhibitors

Cited by 565 publications

References 86 publications

Small-Molecule Inhibitors of Myosin Proteins

Small-Molecule Inhibitors of Myosin Proteins

Inhibition of Bacterial Carbonic Anhydrases as a Novel Approach to Escape Drug Resistance

A Systematic Review on Antitumor Agents with 1, 3, 5-triazines

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